Another important immunosuppressive activity of TGFβ could be its

implication in the development of regulatory T cells. TGFβ promotes the conversion of naive CD4+T cells to Treg cells by induction of selleck product transcription factor FoxP3[131-133]. Several reports have indicated an essential role for both Smad2 and Smad3 transcription factors in TGFβ-mediated induction and maintenance of Foxp3 expression[134-137]. For instance, it was demonstrated that Smad2 and Smad3 double deficiency lead to complete ablation of FoxP3 upregulation by TGFβ, suggesting a functional redundancy between these two transcription factors in the induction of Tregs[137]. A recent paper has shown that both TGFβ1 and prostaglandin E2 derived from MSCs

contributed to allogeneic MSCs induction of CD4+CD25+ FoxP3+ regulatory T cells that possess the ability to suppress alloantigen-driven proliferative responses in a mixed lymphocyte reaction[46]. Later, MSC-derived TGFβ1 was reported to be largely responsible for the increase in Treg frequency based on knockdown studies, thereby protecting breast cancer cells from immune clearance[138]. Recently, a mouse model of ragweed-induced asthma was described in which iv injected MSCs were capable of suppressing Th2-driven allergic responses via secretion of TGFβ[139]. The results suggested that IL-4 and/or IL-13 were able to activate the STAT6 pathway in MSCs which resulted in an increase of their TGFβ production. It seemed that TGFβ secreted by MSCs could mediate its beneficial effects (i.e., inhibition of eosinophil infiltration and excess mucus production in the lung, decreased levels of Th2 cytokines (IL-4, IL-5 and IL-13) in bronchial lavage and lowered serum levels of Th2 immunoglobulins (IgG1 and IgE), either alone or together with recruited Treg cells[139].

CHEMOKINES Chemokines are a family of structurally related peptides with comparatively small molecules (7,5-12,5 kDa) with chemoattractive properties[140]. Their physiological role is participation in processes like regulation Dacomitinib of inflammation, cell differentiation and migration of immune cells, as well as angiogenesis[141]. Chemokines are produced and secreted by various cell types as a response to pro-inflammatory stimuli with the aim to attract and activate neutrophils, monocytes, lymphocytes and other effector cells to sites of infection[140]. It has been established that in vitro cultured MSCs constitutively secrete a multitude of different members of the chemokine family, such as CCL2 (MCP-1), CCL3 (MIP-1α), CCL4 (MIP-1β), CCL5 (RANTES), CCL7 (MCP-3), CCL20 (MIP-3α), CCL26 (eotaxin-3), CXCL1 (GROα), CXCL2 (GROβ), CXCL5 (ENA-78), CXCL8 (IL-8), CXCL10 (IP-10), CXCL11 (i-TAC), CXCL12 (SDF-1) and CX3CL1 (fractalkine)[142].